Phase Ib study of sabatolimab (<scp>MBG453</scp>), a novel immunotherapy targeting <scp>TIM‐3</scp> antibody, in combination with decitabine or azacitidine in high‐ or very high‐risk myelodysplastic syndromes
Authors: Andrew M. Brunner, Jordi Esteve, Kimmo Porkka, Steve Knapper, Elie Traer, Sebastian Scholl, Guillermo Garcia‐Manero, Norbert Vey, Martin Wermke, Jeroen J. W. M. Janssen, Rupa Narayan, Shaun Fleming, Sun Loo, Natalia Tovar, Mika Kontro, Oliver G. Ottmann, Purushotham Naidu, Haiying Sun, May Han, Roisin White, Na Zhang, Anisa Mohammed, Catherine A. Sabatos‐Peyton, David P. Steensma, Mikael L. Rinne, Uma M. Borate, Andrew H. Wei
Journal: American Journal of Hematology (2023)

The safety and efficacy of sabatolimab, a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), was assessed in combination with hypomethylating agents (HMAs) in patients with HMA-naive revised International Prognostic System Score (IPSS-R) high- or very high-risk myelodysplastic syndromes (HR/vHR-MDS) or chronic myelomonocytic leukemia (CMML). Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia. To the Editor: Patients with higher-risk myelodysplastic syndromes/neoplasms (MDS) and chronic myelomonocytic leukemia (CMML) have poor prognoses and need novel therapies that produce durable responses with sustained clinical benefit.1-4 Initial therapy for higher-risk MDS usually includes a hypomethylating agent (HMA), either azacitidine or decitabine,5 but benefits are modest, with <20% of patients achieving complete remission (CR) and a median duration of any response <15 months.6, 7 Patients with CMML treated with HMAs8 also have poor outcomes.9 T-cell immunoglobulin domain and mucin domain-3 (TIM-3)10 are expressed on immune cells and myeloid leukemic cells, and function as an inhibitory surface receptor regulating innate and adaptive immune responses, as well as promoting leukemic stem cell (LSC) self-renewal through interaction with galectin-9.11-15 Increased TIM-3 expression on leukemic progenitors has been described at the time of leukemic progression, suggesting the TIM-3 pathway may be involved in disease transformation to acute myeloid leukemia (AML).16, 17 Conditional knockout of TIM-3 on dendritic cells (DCs) promotes strong antitumor immunity.18 Sabatolimab, a novel monoclonal antibody targeting TIM-3, may interact with the dysregulated immune microenvironment in MDS, and directly with TIM-3-expressing leukemic progenitors.11, 19, 20 Early studies indicate the pharmacokinetic and safety profile of sabatolimab monotherapy is favorable for combination with standard of care therapies in the management of patients with myeloid malignancies.21-23 This Phase Ib trial of sabatolimab + HMA was conducted to evaluate safety, response rate by revised International Working Group (IWG) criteria, and durability of response in patients with high- or very high-risk MDS (HR/vHR-MDS) or CMML.24 This was a Phase Ib, multi-arm, open-label, multicenter study of sabatolimab for patients with AML, HR-/vHR-MDS, or CMML (NCT03066648). This study is focused on the sabatolimab + HMA combination in patients with HR-/vHR-MDS or CMML (Table S1 and Figure S1). The primary objective was to evaluate the safety/tolerability of this combination. Secondary objectives included efficacy, immunogenicity, and effect on modulation of immune cell markers in blood and paired bone marrow samples.33 Further details on the design and methodology of the study are provided in Appendix S1. The study was conducted in accordance with ICH Harmonized Tripartite Guidelines for Good Clinical Practice and the Declaration of Helsinki; written informed consent was obtained from each patient. Between July 6, 2017 and February 15, 2021, 53 patients with HR/vHR-MDS (HR-MDS, n = 32; vHR-MDS, n = 21) and 15 patients with CMML were enrolled. At the September 6, 2021 data cutoff, 34 and 19 patients had received sabatolimab in combination with azacitidine or decitabine, respectively. Baseline characteristics for patients with HR/vHR-MDS or CMML are reported in Table S2. At data cutoff, treatment in patients with HR/vHR-MDS was ongoing in nine patients (17.0%; Table S3). The most common reasons for treatment discontinuation were progressive disease (PD, 30.2%) or allogeneic transplantation (24.5%). Disposition data for patients with CMML are in Table S4. Sabatolimab dose selection and presence of anti-drug antibodies are described in Appendix S1. In patients with HR/vHR-MDS, common adverse events (AEs; all grades, regardless of relationship to study drug) were constipation (56.6% of patients), thrombocytopenia (56.6%), nausea (54.7%), neutropenia (47.2%), and anemia (45.3%) (Table S5 and Figure S2). Serious AEs were reported in 31 patients (58.5%; Table S5). Seven patients with HR/vHR-MDS had possible immune-mediated AEs (imAEs; time to onset, 18–481 days; Table S6 and Appendix S1). Sabatolimab dose interruption occurred in 21 (40%) patients (Table S5). AEs leading to sabatolimab discontinuation were reported in one patient (1.9%): a 75-year-old man with neutropenic colitis suspected to be related to study treatment discontinued treatment and died of septic shock. No other treatment-related deaths were reported. Possible imAEs leading to treatment interruption were reported in two patients (43.8%). Treatment-related AEs and possible imAEs are reported in Tables S7 and S8. The safety profile in patients with CMML treated with sabatolimab + HMA was consistent with those with HR/vHR-MDS (Figure S3 and Table S9). Safety data for a cohort of patients (n = 8) on sabatolimab monotherapy are in Tables S10 and S11. Among 51 evaluable patients with HR/vHR-MDS, overall response rate (ORR) was 56.9% (95% confidence interval [CI], 42.2%–70.7%); 19.6% of patients achieved CR, 23.5% achieved bone marrow CR (mCR; 11.8% of all evaluable patients achieved mCR + hematologic improvement [HI]), 3.9% achieved partial response (PR), and 9.8% achieved stable disease (SD) with HI (Figure 1A). The median time to response (TTR) was 2.0 months (range, 1.7–9.6). Among patients who achieved CR, mCR, or PR, the median duration of response (mDOR) was 17.1 months (95% CI, 6.7–not estimable [NE]; Figure 1A,B); mDOR among patients who achieved CR was 19.3 months (95% CI, 12.1–NE). The mDOR among patients who achieved mCR with HI was 7.9 months (95% CI, 3.0–NE) and not estimable among patients who achieved mCR without HI and PR. Twenty patients experienced events considered progression and 33 patients were censored for progression-free survival (PFS), 20 of whom started new lines of therapy (which was considered a censoring event for PFS), including transplant. Median PFS was 17.2 months (95% CI, 6.6–23.3); the estimated 12-month PFS rate was 54.0% (95% CI, 33.0%–71.0%) (Figure 1A,C). Efficacy data in patients with HR/vHR-MDS treated with sabatolimab monotherapy are reported in Table S13. The impact of blast burden, TP53 and other ELN 2017 adverse-risk mutations,25 and imAEs on treatment response are described in Appendix S1. Among 15 evaluable patients with CMML, ORR was 66.7% (95% CI, 38.4%–88.2%) and mDOR was 5.6 months (95% CI, 3.0–NE; Table S12). Post-study outcome analyses on overall survival (OS) and responses in patients who proceeded to allogeneic hematopoietic cell transplantation are described in Appendix S1. Across the entire cohort, the median OS was 26.7 months. Of the 19 patients who underwent allogeneic transplant, the post-transplant survival rate at 2 years was 69%. Currently approved therapies for treating higher-risk MDS and CMML are palliative; complete responses to treatment are infrequent, and responses are generally short-lived.8, 26 In this Phase Ib study, sabatolimab did not add clinically important toxicity to standard-of-care HMA treatment in patients with HR/vHR-MDS or CMML, resulting in few sabatolimab dose interruptions and very rare discontinuations, suggesting that the combination has the potential to yield more durable responses without additional safety concerns. A challenge in treating patients with MDS or CMML is that many patients are elderly and may harbor comorbid conditions that preclude intensive treatment options.8, 27, 28 AEs observed with sabatolimab + HMA were consistent with those previously reported for HMA alone. Randomized studies are underway to better characterize any added toxicity from combination therapy.29 Possible imAEs were specifically examined because sabatolimab inhibits TIM-3, which is an inhibitory immune receptor; these AEs are thought to be secondary to the disruption of immunologic self-tolerance.30 Few patients had clinically significant possible imAEs, with no grade ≥ 3 events reported. Interestingly, all seven patients with possible imAEs achieved a response, although only ~25% of responders experienced possible imAEs. This observed relationship between response and possible imAEs needs further confirmation. Because of concerns related to exposure to immunological therapies around transplant, we also assessed patients who received sabatolimab and subsequently proceeded to allogeneic transplant, noting generally favorable survival given the high-risk disease in this cohort and usual transplant risks; few of these patients experienced severe graft versus host disease. Further data will be important to assess the safety of transplant after sabatolimab exposure. OS with this combination compared with HMA alone is being evaluated in ongoing STIMULUS trials (NCT03946670 and NCT04266301). Duration of clinical responses in patients with HR/vHR-MDS was encouraging compared with historical data, with an mDOR of 17.1 months compared with 10–15 months with HMA alone.6, 7 These longer responses were also observed in patients with adverse-risk mutations (mDOR 21.5 months). The duration of responses observed with sabatolimab + HMA in the overall (17.1 months) and TP53-mutated patient (21.5 months) populations is encouraging, although confirmation in larger randomized studies with longer follow-up is needed. These findings are consistent with a putative immunomodulatory component to the mechanism of action for sabatolimab. Based on this study and others,23, 31 doses of 400 mg every 2 weeks (Q2W) and 800 mg every 4 weeks (Q4W) were selected for further evaluation. The 800 mg Q4W dosing regimen of sabatolimab was then established based on pharmacokinetics/pharmacodynamics analysis, convenience of dosing, and lack of differences in toxicity or responses.21 Limitations of this Phase Ib study are the non-randomized open-label design, absence of HMA-alone control arms, and heterogeneity of the patient population. In the subsequent STIMULUS-MDS1 study (NCT03946670), CR and PFS were not statistically different between patients with intermediate-risk (IR)/HR/vHR-MDS given sabatolimab + HMA versus HMA alone. Considering the potential of a delayed-onset benefit and that OS is more indicative of the effect of an immunomodulatory therapy compared with short-term CR, the study is still ongoing to collect long-term safety and survival data,32 and the STIMULUS-MDS-2 study (NCT04266301), which has a primary OS endpoint, has completed enrollment. In conclusion, sabatolimab could be combined with standard HMA therapy in patients with HR/vHR-MDS or CMML, including patients with adverse-risk mutations, with safety comparable to HMA monotherapy and early signals of extended duration of responses. We identified a dose of sabatolimab (800 mg Q4W) in combination with HMA for future studies. The results underscore the potential of TIM-3 as a therapeutic target in myeloid malignancies and support ongoing exploration of sabatolimab treatment in various combination regimens. All authors contributed equally to the writing of the manuscript and read and approved the final manuscript. Medical writing support was provided by Bridget Sackey-Aboagye, PhD, of Healthcare Consultancy Group, and was funded by Novartis Pharmaceuticals Corporation. Andrew M. Brunner has received consulting fees from Acceleron, Agios, BMS/Celgene, Gilead, Keros Therapeutics, Novartis, Takeda, and Taiho. His research is supported by the Edward P. Evans Foundation and NIH NCI. Jordi Esteve has received consulting fees from Abbvie, Novartis, Astellas, Jazz Pharmaceuticals, BMS-Celgene, Pfizer, Amgen, and Daichii-Sankyo; and research grants to his institution and cooperative group CETLAM from Novartis, Pfizer, and Jazz Pharmaceuticals. Kimmo Porkka has received honoraria from AbbVie, Astellas Pharma, BMS/Celgene, Incyte, Novartis, and Pfizer; and has received research funding to his institution from AbbVie BMS/Celgene, Incyte, Novartis, and Pfizer. Steve Knapper reports consultancy and speakers bureau participation for Pfizer, Astellas, Jazz, and Novartis; and research funding from Novartis. Elie Traer serves on ad boards for Astellas, AbbVie, Servier, Daiichi-Sankyo, Rigel; and receives research funding from Incyte, Schrodinger, Prelude Therapeutics, and AstraZeneca. Sebastian Scholl reports research funding from Novartis; advisory boards for Novartis, Pfizer, and Amgen. Guillermo Garcia-Manero has nothing to disclose. Norbert Vey has nothing to disclose. Martin Wermke reports consultancy, research funding, and honoraria from Novartis, Roche, Pfizer, and BMS. Jeroen J. W. M. Janssen reports research support from Novartis and BMS to institution; he is president of the Apps for Care and Science, a nonprofit foundation that develops the HematologyApp and is supported by AbbVie, Alexion, Amgen, Astellas, Astra Zeneca, BMS, Daiichi-Sankyo, Janssen-Cilag, Olympus, Incyte, Sanofi Genzyme, Servier, Jazz, Takeda; honoraria for advisory boards from AbbVie, Novartis, Pfizer, and Incyte to institution. Rupa Narayan reports Novartis research funding to institution. Shaun Fleming has nothing to disclose. Sun Loo has nothing to disclose. Natalia Tovar has nothing to disclose. Mika Kontro reports consultancy for Astellas Pharma; research funding from AbbVie; and membership on an entity's Board of Directors or advisory committees for AbbVie, Astellas Pharma, BMS/Celgene, and Jazz Pharmaceuticals. Oliver G. Ottmann has received honoraria from Incyte, Novartis, Amgen and Celgene, and has received research funding to his institution from Incyte, Roche, and Celgene. Purushotham Naidu reports employment with Novartis. Haiying Sun HS reports employment with Novartis and is a Novartis stockholder. May Han has nothing to disclose. Roisin White reports employment with Novartis. Na Zhang reports employment with Novartis before when NZ was working on this project. Anisa Mohammed reports employment with Novartis and is a Novartis stockholder. Catherine A. Sabatos-Peyton was an employee of Novartis and holds patents on TIM-3 through BWH/Harvard and CoStim.Novartis. CAS-P is employed by and has options in Larkspur Biosciences. David P. Steensma reports employment with Novartis when working on this project. Mikael L. Rinne reports prior employment with Novartis and consultancy for Qiagen; reports current employment with Blueprint Medicines and is a Blueprint Medicines stockholder. Uma M. Borate reports Consulting for Kura Oncology. Andrew H. Wei has served on advisory boards for Novartis, Janssen, Amgen, Roche, Pfizer, AbbVie, Servier, Celgene-BMS, MacroGenics, Agios, and Gilead; receives research funding to the institution from Novartis, AbbVie, Servier, Celgene-BMS, AstraZeneca, and Amgen; serves on speakers bureaus for AbbVie, Novartis, and Celgene; receives royalty payments from the Walter and Eliza Hall Institute of Medical Research related to venetoclax. 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